Malaria burden is compounded by the HIV epidemic, which is most prevalent in malaria endemic areas, notably Sub-Saharan Africa. Evidence suggests that each infection enhances the pathogenicity of the other. Despite the overlap between HIV and malaria, the antimalarial impact of drugs used to treat and manage HIV infection remains largely unexplored. A greater understanding of these effects is urgently needed as more patients are started on antiretroviral therapy, not only as these drugs might have direct anti-parasite effects, but also as stage-specific parasite effect may translate into immunologic effects in the host. If such medications used in the treatment and management of HIV patients are deemed to be suited to causal (liver stage cidal)or suppressive (asexual blood stage cidal)anti-malarial prophylaxis, their use may become more standardized and possibly timed to stimulate malaria-specific immunity. We hypothesize that: 1) early treatment of rodent malaria infection with a variety of antimalarials and antiretrovirals that have causal or suppressive prophylaxis effects can induce protective immunity against parasites;2) protective immunity can similarly be achieved in humans who undergo experimental malaria infection in conjunction with different drug regimens;and 3) the use of drugs with causal or suppressive prophylaxis effects may contribute to naturally acquired protective immunity in African children. Based on these hypotheses, we propose the following Aims for this project: Specific Aims: Specific Aim 1. After characterizing stage-specific effects of HIV-drugs, assess the degree and duration of protective immunity induced by different HIV-drugs given after sporozoite inoculation of mice. Specific Aim 2. Examine whether causal prophylaxis with different HIV-drugs given after sporozoite challenge will similarly induce protective immunity in humans. Specific Aim 3: Determine whether HIV-drugs with causal prophylaxis or suppressive prophylaxis effects are related to malaria resistance in naturally exposed HIV-infected children. During the past year, we have demonstrated the following in each of the following categories of HIV-related drugs: o HIV Protease inhibitors (PIs): -Liver Stage: (we have previously assessed HIV PI effect on liver stage parasites in the rodent Plasmodium model, P. yoelii, and demonstrated that HIV PIs have potent anti-liver stage effect at levels below clinical relevance). -Asexual Blood Stage: PIs have reduced efficacy against asexual blood stage P. yoelii. We are evaluating utility of an alternate strain of rodent parasite, P. chabaudi for future suppressive prophylaxis regimens, since P. chabaudi is a parasite that mimics the dynamics of P. falciparum (all life cycle stages present at a given time are synchronous). We are also evaluating the maximum HIV PI dose to produce sterilization of parasites (full causal prophylaxis) in Plasmodium-sporozoite-infected mice. -Transmission Stage: PIs have an anti-sexual stage effect and incubation of late sexual parasite stages results in reduced mosquito infectivity when assessed by membrane feed transmission assays, whereas NNRTIs do not. Papers being drafted/reviewed by co-authors for planned submission. o HIV Non-nuceloside reverse transcriptase inhibitors (NNRTIs) -Liver Stage: NNRTIs have effect in reducing liver stage parasite burden, and correspondingly increase time to detection of parasites in the blood in P. yoelii. -Asexual Blood Stage: NNRTIs do not have anti-blood stage in P. falciparum Growth Assays. Papers being drafted/reviewed by co-authors for planned submission. -Transmission Stage: NNRTIs do not have an anti-sexual stage effect and do not result in reduced mosquito infectivity when assessed by membrane feed transmission assays, in direct contrast to HIV PIs. Papers being drafted/reviewed by co-authors for planned submission. o Trimethoprim-sulfamethoxazole (TMP-SMX) -Liver Stage: TMP-SMX has sterilizing effect on liver stage parasites at clinically relevant concentrations and has potent anti-blood stage effect, in P. yoelii. -Asexual Blood Stage: Co-trimoxazole effect at clinically relevant concentrations in growth assays of P. falciparum is currently being characterized. We are also assessing the effects of co-trimoxazole on the development of malaria-specific immunity after several exposures to live sporozoites in rodent models. -Transmission Stage: Co-trimoxazole has effect in reducing transmission in the mosquito stages, but has no effect on sexual stages in the host, at clinically relevant concentrations. Papers being drafted/reviewed by co-authors for planned submission.